This invention comprises novel pyrazine amides which are useful as eukalemic diuretics.
A variety of agents are available for use in treating hypertension. One particular class of such agents is diuretics. Diuretics are used for a variety of purposes, for example, reduction of fluid from the body and reduction of sodium levels in the body, for example, in the treatment of hypertension and edema. An example of a diuretic is 2-(aminomethyl)-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride of formula I:
(Formula set out on pages following Examples) I discussed in U.S. Pat. No. 4,029,816 to Cragoe et al; and Stokker, G.E., J. Med. Chem., 1980, 23, 1414-1427. Additional diuretics include hydrochlorothiazide and chlorthalidone.
A problem with some diuretics is the reduction of serum potassium levels and complications caused from reductions of potassium beyond levels needed for maintaining physiological functions. Thus, some diuretics are used in conjunction with a potassium conserving agent such as 3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazine carboxamide monohydrochloride, dihydrate of formula II:
(Formula set out on pages following Examples) II shown in U.S. Pat. No. 3,577,418 to Cragoe et al which is used in conjunction with, for example, thiazide diuretics.
There is thus a need for a single agent which is an effective but potassium-conserving (isokalemic, also called eukalemic) diuretic, such that it obviates the problems associated with hypokalemia (potassium depletion) and hyperkalemia (potassium buildup) without the need for taking multiple therapeutic agents.
A series of pyrazine-carboxamides has been described in U.S. Pat. No. 4,085,211 as eukalemic agents possessing diuretic and natriuretic properties. We have now discovered (and this is a basis for our invention) that, surprisingly, certain aminomethylphenol containing pyrazine amides of the formula III defined below possess eukalemic diuretic properties and are of value in treating those diseases and conditions in which a eukalemic diuretic effect is required, for example in treating edema, hypertension and/or related conditions.